Type 2 diabetes is characterized by insulin resistance and disordered beta-cell function, especially a defect in glucose-stimulated insulin-secretion. Insulin receptors and signaling proteins are found within the beta-cells themselves. Recent evidence in rodents suggests the insulin signaling pathway is functional in islets and is important for glucose sensing. The physiologic role of insulin signaling within beta-cells in humans remains unknown. Our preliminary studies demonstrate that in healthy humans beta-cells are insulin sensitive tissues and raising circulating insulin levels by exogenous insulin administration can enhance glucose induced insulin secretion. We hypothesize that dysfunctional insulin signaling, i.e. insulin resistance, at the level of the beta-cell may be one mechanism underlying blunted insulin secretion in persons with type 2 diabetes and insulin resistant syndromes, which would be manifest as reduced insulin potentiation of glucose induced insulin secretion. We propose to further our understanding of insulin's effects on the beta-cell in healthy persons and to determine whether insulin potentiation of glucose induced insulin secretion is blunted in persons with type 2 diabetes. We demonstrate insulin potentiates glucose induced insulin secretion in the setting of suppression of circulating FFA. Several studies suggest an essential role for FFA in both basal and glucose stimulated insulin secretion, while other studies suggest that excess FFA are lipotoxic to the a-cell. To test whether replacement of FFA will enhance insulin potentiation of glucose induced insulin secretion, or whether the response is secondary to the suppression of circulating FFA, we will evaluate the role of free fatty acids in insulin potentiation of glucose induced insulin production. We demonstrate a marked increase in glucose disposal rates with dextrose administration following insulin pre-exposure. We will evaluate whether this occurs within hepatic or muscle tissues using positron emission tomography imaging. To better understand the molecular pathways underlying these processes, mechanistic studies will be conducted in control and insulin receptor deficient islets, in vitro. These studies may provide a unifying explanation linking the combined defects in insulin secretion and action that underlie type 2 diabetes.